Analysis of the Biological Effects of Extracts from the Plant Species Cannabis sativa (Linnaeus) in Models of Protein Aggregation Studies Associated with Neurodegenerative Diseases
Cannabis sativa, neurodegenerative diseases, α-synuclein, beta-amyloid, Saccharomyces cerevisiae, H4 cells.
Neurodegenerative diseases, in general, are characterized by progressive loss of vulnerable neurons and are related to conformational abnormalities of proteins, such as the formation of oligomers containing the α-synuclein protein in Parkinson's disease (PD) and the β-amyloid peptide in Alzheimer's disease (AD). The plant C. sativa has a diverse chemical profile depending on its genotype, including various classes of substances such as cannabinoids, flavonoids, terpenes, and alkaloids. However, most research addresses the role of phytocannabinoids in isolation. In this study, we evaluated the effects of four C. sativa extracts with different phytocannabinoid chemical profiles in two cellular models that reproduce alterations in cellular homeostasis common during the cellular phase of PD and AD. We used Saccharomyces cerevisiae strains with a deletion in the Yap1p transcription factor and transformed with plasmid DNA expressing aSyn and Aβ42, as well as genetically modified human cells (H4) expressing aSyn. Phytochemical characterization revealed extracts rich in tetrahydrocannabinol – THC (69.88%), cannabidiol – CBD (52.64%), and cannabinol – CBN (47.38% and 58.64%), and we concluded that, regardless of these percentages, all C. sativa extracts showed antioxidant activity independent of the endogenous antioxidant defense system, and reversed the redox imbalance caused by proteins associated with neurodegenerative diseases. However, the extracts were not able to protect against mitochondrial damage caused by aSyn expression, although they protected mitochondria affected by the Aβ42 peptide, suggesting selectivity towards the expressed protein. Furthermore, the extracts reduced the number of intracellular inclusions in H4 cells and increased the number of inclusion-free cells, demonstrating protective biological activity against toxicity caused by aSyn production in H4 cells. C. sativa extracts showed promising effects in modulating aSyn inclusions and in intracellular antioxidant protection, but their role in mitochondrial regulation still needs further investigation.